Chapter 182 – Posterior Uveitis of Unknown Cause

• Inflammatory disorders of unknown cause that involve the outer retina, retinal pigment epithelium, or choroid, or a combination, in one or both eyes of patients in their second to sixth decades of life.

KEY FEATURES

• Unknown cause with negative serological evaluation.

• White or yellow spots in the posterior segment.

ASSOCIATED FEATURES

• Unilateral or bilateral, depending on the disease.

• Second to sixth decades of life.

• Variable inflammatory cells in the anterior chamber and vitreous humor, depending on the disease.

• Usually self-limited course but variable prognosis, depending on the disease.

INTRODUCTION

Several disorders occur that affect the retina and choroid. They are multifocal in nature, are associated with whitening in the retina, typically affect patients between the second and sixth decades of life, and despite exhaustive evaluation, have no known cause. These entities carry the label white spot syndromes or inflammatory multifocal chorioretinopathies. The latter, more descriptive, term is preferred. These entities include acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), birdshot chorioretinopathy, serpiginous choroiditis, multifocal choroiditis and panuveitis, subretinal fibrosis and uveitis, punctate inner choroidopathy, acute macular neuroretinopathy, acute retinal pigment epitheliitis, unilateral acute idiopathic maculopathy, acute zonal occult outer retinopathy (AZOOR) and, more recently, relentless placoid chorioretinitis and unifocal helioid choroiditis. All affect the retina, retinal pigment epithelium (RPE), or choroid. They rarely have signs of anterior uveitis, yet these entities are important causes of decreased vision in young patients. Although some of these disorders are self-limited and have good visual outcomes, others are associated with serious retinal and choroidal sequelae and can result in visual loss. In the future, these entities may be proven to be autoimmune or infectious or both.

ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY

EPIDEMIOLOGY AND PATHOGENESIS

APMPPE is an inflammatory disease, usually bilateral, that affects the choriocapillaris, RPE, and outer retina of otherwise healthy young adults in the second and third decades of life.

Figure 182-1 Fundus view of the right eye of a 17-year-old man who has acute posterior multifocal placoid pigment epitheliopathy. Numerous creamy, white-yellow, placoid lesions are seen in the posterior pole. Note the pigmenting lesion in the inferior macula that has started to heal.

Men and women are affected equally. The disease may be preceded by a viral prodrome. [1]

OCULAR MANIFESTATIONS

After a short viral prodrome, symptoms of mild myelomeningeal encephalitis, namely meningismus, headaches, and transient hearing loss, may develop. [2] [3] [4] Patients subsequently develop a sudden, painless loss of vision in one or, more typically, both eyes.[1]

The characteristic choroidal lesions and fluorescein angiographic pattern are usually sufficient to make the diagnosis of APMPPE. The absence of substantial anterior chamber or vitreous inflammation in a young, healthy patient who has a viral prodrome with typical fundus lesions is highly suggestive of APMPPE. Fluorescein angiography shows early hypofluorescence of these white placoid lesions with late staining of these same lesions ( Figs. 182-2 and 182-3 ). [1] Indocyanine green angiography also shows hypofluorescent lesions. Laboratory evaluation of these patients is usually unrewarding (except for the findings of protein and cells in the spinal fluid, and rare hematuria) and usually not necessary.

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Figure 182-2 Hypofluorescence of acute lesions and early hyperfluorescence of healing lesions. Laminar, venous phase fluorescein angiogram of the right eye of the patient shown in Figure 182-1 .

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of APMPPE is given in Box 182-1 . The creamy lesions of APMPPE are unique but occasionally may be confused with metastatic tumors, viral retinitis, and toxoplasma retinochoroiditis. In APMPPE, however, the creamy lesions are flat and are not associated with significant vitreitis. Healed APMPPE may leave behind variable amounts of pigmentary changes in the posterior pole, which can be difficult to differentiate from other inflammatory conditions.

SYSTEMIC ASSOCIATIONS

Cerebral vasculitis and cerebrospinal fluid pleocytosis have been reported in patients who have APMPPE. [2] [3] [4] [5] Rarely this may be fatal. Acute nephritis occurred concurrently with APMPPE in one patient.[8] It is thought that one or more viruses may be the causative agents of APMPPE.[1] Serological evidence of adenovirus type 5 infection has been documented with APMPPE. [9]

PATHOLOGY

The histopathology of eyes that have APMPPE has not been studied. However, because the placoid lesions result in variable retinal pigment epithelial alterations with usually good visual acuity, it is thought that lesions occur either at the level of the RPE or perhaps the choriocapillaris.

TREATMENT

Usually no treatment is necessary; the disease tends to be self-limited. Some ophthalmologists use systemic corticosteroids, although no convincing evidence exists that corticosteroids speed visual recovery or improve visual outcome.

COURSE AND OUTCOMES

Most patients who have APMPPE have a self-limited course of 2–6 weeks. Visual acuity is usually diminished during the early part of the disease and may vary from 20/20 (6/6) to 20/400 (6/120), depending on the location of the placoid lesions. In most patients vision improves to near-normal levels during the first 2–3 weeks after the onset of symptoms. Patients, however, may continue to complain of difficulty with reading or of scotomas

Figure 182-3 Late hyperfluorescence of both acute and healing lesions. Late arteriovenous phase fluorescein angiogram of the same eye as shown in Figures 182-1 and 182-2 .

in the central visual field. The placoid lesions resolve over a period of 2–6 weeks. Significant macular retinal pigment epithelial mottling and alterations remain after the resolution of these placoid lesions.[1] Rare cases of persistent, chronic, or recurrent APMPPE have been reported in which severe retinal pigment epithelial alterations may occur.[10] This can result in severe visual loss. Choroidal neovascularization is an uncommon complication of APMPPE but has been reported.[11] Disruption of Bruch’s membrane and the choriocapillaris probably occurs less frequently in APMPPE than with serpiginous choroidopathy.

MULTIPLE, EVANESCENT, WHITE DOT SYNDROME

EPIDEMIOLOGY AND PATHOGENESIS

MEWDS is an inflammatory chorioretinopathy that affects mainly young, healthy women in the second to fifth decades of life. A flu-like illness is present in about one half of the patients.[12]

OCULAR MANIFESTATIONS

Patients who have MEWDS have acute, unilateral, painless visual loss.[12] Bilateral cases have been reported, but they tend to be asymmetrical.[13] Patients often complain of a scotoma and associated shimmering photopsias, often in the temporal visual field. Ocular findings include a variable amount of vitreitis, optic

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Figure 182-4 Right eye of a woman who has multiple, evanescent, white dot syndrome. Note multiple white spots throughout posterior pole and granular appearance to fovea.

disc edema and, characteristically, multiple white spots at the level of the RPE or deep retina in the posterior pole ( Fig. 182-4 ). Retinal vascular sheathing may be present also. A characteristic granular appearance to the fovea is present acutely, and the fovea usually does not return to a normal appearance (see Fig. 182-4 ).[12]

DIAGNOSIS

Diagnosis is made by the typical ocular manifestations of the disease. Visual field testing may reveal enlargement of the blind spot.[12] [14] Fluorescein angiography may reveal leakage from disc capillaries and late punctate staining of the RPE, sometimes in the shape of a wreath ( Fig. 182-5 ).[12] [14] Indocyanine green angiography demonstrates multiple hypofluorescent areas in the posterior pole. These hypofluorescent areas suggest that MEWDS affects the outer retina or RPE (blockage), or the underlying choroid (nonperfusion).[15] Electrophysiological studies may reveal a profoundly decreased a-wave amplitude on the electroretinogram and early receptor potential amplitudes in the acute phase of the disease, which suggests widespread photoreceptor dysfunction.[16] During the recovery phases, these amplitudes return to normal. In addition, prolonged regeneration kinetics of the RPE also are present in the acute phases of the disorder. [16] The exact mechanisms of visual loss in MEWDS are not understood well but may represent photoreceptor, RPE, and optic nerve dysfunction.

DIFFERENTIAL DIAGNOSIS

Acute idiopathic blind spot enlargement may occur alone or with MEWDS, multifocal choroiditis, or acute macular neuroretinopathy. It is thought that acute idiopathic blind spot enlargement may be either a common factor that links all of these disorders or part of the spectrum of diseases that include all of these inflammatory chorioretinopathies ( Box 182-2 ). [17] [18] [19] Systemically, viral prodrome may occur in up to 50% of patients.[12]

COURSE AND OUTCOMES

Because MEWDS has a self-limited course, no specific treatment is necessary.[12] The white dots fade and disc edema gradually resolves, usually within 2–6 weeks of the onset of symptoms and

ocular findings. Visual acuity gradually returns to baseline levels. The temporal scotoma and photopsias may take considerably longer to resolve (several months). [12] Recurrences are uncommon but have been reported.[13] Visual prognosis is good even among patients who have recurrences. An uncommon association of MEWDS with acute macular neuroretinopathy has been described.[20] Rare instances of choroidal neovascularization following MEWDS have been reported, [21] which may be confused with idiopathic choroidal neovascularization, because the white dots are no longer present.[20]

SERPIGINOUS CHOROIDITIS

EPIDEMIOLOGY

Serpiginous choroiditis has been described under many different names, including helicoid and geographical choroidopathy; current understanding of this disease is limited. The condition affects healthy patients from the second to seventh decades of life. Men and women are affected equally. [22] [23] [24]

OCULAR MANIFESTATIONS

Patients who have serpiginous choroiditis typically experience paracentral or central scotomata with vision loss. Some lesions may be asymptomatic. Ocular examination may reveal some inflammatory response in the anterior chamber or vitreous humor. [22] [23] [24] [25] The typical lesions begin either in the peripapillary region or macula and eventually affect both eyes.

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Figure 182-6 Fundus view of the right eye of a 57-year-old woman who has early serpiginous choroiditis. A peripapillary serpentine lesion extends into the fovea. Visual acuity is 20/60 (6/18).

Differential Diagnosis of Serpiginous Choroiditis

Acute posterior multifocal placoid pigment epitheliopathy

Relentless placoid chorioretinitis

Multifocal choroiditis and uveitis

Birdshot retinochoroidopathy

Ocular histoplasmosis syndrome

New lesions usually appear at the edges of older ones. The disease has a progressive, step-wise course. New lesions appear slightly yellow to gray in color, and the overlying retina may be thickened. Often these lesions progress in a centripetal, helicoid, or serpentine-like fashion from the peripapillary area or macula into the remainder of the posterior pole ( Fig. 182-6 ). [23] [24] With time these lesions become atrophic, with disappearance of the RPE, choriocapillaris, and choroid.[26] In patients who have macular serpiginous choroiditis, the initial lesions are seen in the macula with no initial peripapillary activity.[27] Subretinal hemorrhage and serous retinal detachment as a result of choroidal neovascularization can occur in eyes with serpiginous choroiditis.[22] [28]

DIAGNOSIS

Diagnosis is established by the typical clinical appearance of the lesions. Fluorescein angiography demonstrates early hypofluorescence and late hyperfluorescence of active lesions. Indocyanine green angiography also shows hypofluorescent active lesions. Atrophic lesions show diffuse loss of pigment, choroidal vessels, and late staining on fluorescein angiography. Retinal vascular staining also may occur adjacent to active lesions. Associated choroidal neovascularization shows late leakage and often arises from the borders of old scars.[28]

Laboratory evaluation of these patients is invariably unrewarding. An association of serpiginous choroiditis and tuberculosis has been suggested. However, treatment with antimicrobial agents has made no difference to the course of the disease in these patients.[26]

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of serpiginous choroiditis is given in Box 182-3 . The peripapillary scarring seen in serpiginous choroiditis may be difficult to differentiate from inactive multifocal choroiditis and uveitis syndrome and ocular histoplasmosis syndrome. However, serpentine centripetal progression is quite characteristic of serpiginous choroiditis.

PATHOLOGY

The few eyes with serpiginous choroiditis that have been studied histopathologically showed extensive loss of RPE, with destruction of the overlying retina and lymphocytic infiltration of the choriocapillaris and other areas of the choroid.[29]

TREATMENT

The inflammatory nature of this disorder means that systemic and periocular glucocorticoids may be of benefit. However, treatment with these medications acutely does not prevent recurrences. Recurrences may result in progressive macular involvement. Cyclosporin, azathioprine, and other cytotoxic agents also have been used to treat serpiginous choroiditis.[22] [30] [31] Because these medications have associated potential systemic side effects, they should be used with the assistance of a rheumatologist, internist, or oncologist. Choroidal neovascularization has been treated successfully with laser photocoagulation.[28]

COURSE AND OUTCOMES

Many cases of serpiginous choroiditis are relentlessly progressive, and foveal destruction eventually occurs. Central visual acuity is lost in 20% or more of eyes with serpiginous choroiditis.[22] [24] Central visual loss also can occur from choroidal neovascularization, which carries a poor visual prognosis. Long-term immunosuppressive therapy with glucocorticoids, azathioprine, cyclophosphamide, and cyclosporin alone or in combination remains unproved as a way to prevent visual loss.[22] [30]

BIRDSHOT RETINOCHOROIDOPATHY

EPIDEMIOLOGY AND PATHOGENESIS

Birdshot retinochoroidopathy also has been called vitiliginous chorioretinitis. This syndrome affects healthy patients, usually women, between the third and sixth decades of life.[32] Nearly 90% of patients who have birdshot retinochoroidopathy have positive human lymphocyte antigen A29 (HLA-A29) levels. This is the highest association of any HLA antigen with a human disease. Lymphocyte reactivity to retinal S-antigen is also present in these patients, which suggests an autoimmune pathogenesis.[33]

OCULAR MANIFESTATIONS

Patients complain of blurred vision, floaters, central and peripheral photopsias and, later, nyctalopia and color blindness.[32] [34] Vitreous inflammation is present. Multifocal depigmented patches are seen throughout the posterior pole. Disc edema, narrowed retinal vessels, and cystoid macular edema (CME) are present. The creamy lesions typically are small and less than one disc diameter in size; they are scattered throughout the entire fundus, which gives the disease its characteristic name of birdshot retinochoroidopathy ( Fig. 182-7 ). These lesions may be depigmented spots at the level of the pigment epithelium or may represent changes at the level of the photoreceptors or choroid. [32] [34]

DIAGNOSIS

The diagnosis of birdshot retinochoroidopathy is based on age of onset combined with the characteristic ocular findings.[32] [34] Fluorescein angiography reveals disc staining, vascular leakage, and late CME.[32] [34] The hypopigmented patches usually do not

show any significant change in normal background choroidal fluorescence. In the late phases of the angiogram, these hypopigmented lesions do appear mildly hyperfluorescent. These patches are more prominent ophthalmoscopically than angiographically.[32] [34]

Electroretinography reveals bilateral, moderately to severely depressed rod and cone function. Severe cases often demonstrate a totally extinguished electroretinogram. Electro-oculography usually is normal but can be variably subnormal in some patients.[34]

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of birdshot retinochoroidopathy is given in Box 182-4 . Several disorders produce multiple, creamy choroidal lesions. Few are so commonly associated with CME as birdshot retinochoroidopathy. Pars planitis and chronic iridocyclitis can produce CME but are not associated with choroidal lesions. Onset of vitreitis and CME in the fifth and sixth decades is quite characteristic of birdshot retinochoroidopathy.

TREATMENT

Periocular and systemic glucocorticoids have been the mainstay of therapy for patients who have birdshot retinochoroidopathy. Treatment should be considered when visual acuity drops below 20/40 (6/12) as a result of CME. However, glucocorticoids are of limited value in many patients. Vision may continue to deteriorate because of chronic CME. As a result systemic cyclosporin, azathioprine, or low-dose methotrexate may be administered judiciously, with the help of an oncologist, rheumatologist, or an internist for patients who have birdshot retinochoroidopathy and are unresponsive to glucocorticoids.

Figure 182-8 Fundus view of the right eye of a patient who has progressive subretinal fibrosis and uveitis syndrome. Note the extensive submacular fibrosis.

Progressive subretinal fibrosis and uveitis syndrome is an extremely rare entity that occurs primarily in young women who are in the second and third decades of life and otherwise healthy. The subretinal fibrosis and uveitis syndrome is associated with chronic vitreous inflammation and white, fibrotic subretinal lesions, which enlarge and coalesce in a progressive manner to involve most of the retina and choroid ( Fig. 182-8 ). Diagnosis is based mainly on the characteristic ophthalmoscopic appearance.[35] [36]

The differential diagnosis of subretinal fibrosis and uveitis is shown in Box 182-5 . Sarcoidosis, ocular histoplasmosis syndrome, and toxoplasma retinochoroiditis can be differentiated by appearance, clinical course, and laboratory evaluation from subretinal fibrosis and uveitis syndrome. Often the diagnosis of

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subretinal fibrosis and uveitis is made only with disease progression and development of end-stage fibrosis.

PATHOLOGY

Histopathological evaluation of a chorioretinal biopsy specimen from a patient who had subretinal fibrosis and uveitis syndrome revealed a markedly inflamed choroid. A predominance of B cells and plasma cells was noted, as well as the presence of subretinal fibrotic tissue with islands of cells that had the morphological characteristics of retinal pigment epithelial and Müller cells.[37]

TREATMENT

Treatment of this entity with systemic glucocorticoids has been reported to be unrewarding, with eventual progression to complete subretinal fibrosis of the macula.[35] [36] Cytotoxic agents may be helpful. The authors, however, used systemic glucocorticoids successfully to limit the damage in the second eye of one patient who had this entity.

MULTIFOCAL CHOROIDITIS AND PANUVEITIS

EPIDEMIOLOGY

Multifocal choroiditis with panuveitis is a common inflammatory disease that occurs predominantly in women between the second and sixth decades of life. Most cases are bilateral when diagnosed or become bilateral.[38] [39]

OCULAR MANIFESTATIONS

Patients have decreased visual acuity in one or both eyes. Photopsias may be present, and an enlarged blind spot may be symptomatic. Most patients have a variable amount of anterior segment inflammation and vitreitis. The optic discs generally are normal, but the peripapillary RPE usually is disrupted. An area of fibrosis in the shape of a napkin holder may surround the disc. Peripapillary and macular choroidal neovascular membranes can occur.[39] Acute choroidal lesions vary in size in the range of 50–350?m. They may vary in number from several to several hundred, and they can occur in linear clusters or as streak lesions.[40] Acute lesions are yellowish to gray in color and located at the level of the RPE. Older lesions appear atrophic and “punched-out,” with variable amounts of pigment. Retinal pigment epithelial metaplasia with associated fibrosis may be seen.[38] [39]

DIAGNOSIS

Diagnosis is made by clinical examination. The fundus examination findings are reminiscent of ocular histoplasmosis syndrome but with the presence of cells in the vitreous humor. Extensive subretinal proliferation of RPE with fibrosis or clumping is more common with multifocal choroiditis than with ocular histoplasmosis syndrome. Fluorescein angiography reveals early blockage by acute, active, yellow lesions in the choroid, with late staining of these lesions.[39] With progression and atrophy, these lesions show early hyperfluorescence which fades in the late phases of the angiogram. Peripapillary or subfoveal choroidal neovascularization may be seen. CME may be seen in the late phases of the angiogram in some patients. [38] Indocyanine green angiography shows hypofluorescent lesions that may cluster around the optic disc.

The electroretinogram is usually normal or borderline, however in severe cases it may be extinguished. The electro-oculogram is normal.[38]

Visual field testing may reveal an enlarged blind spot and, rarely, other abnormalities.

The differential diagnosis of multifocal choroiditis with panuveitis is shown in Box 182-6 . Ocular histoplasmosis and myopic degeneration are not associated with any vitreitis, unlike multifocal choroiditis.[40A] Other disorders may be much more difficult to differentiate from multifocal choroiditis, often a diagnosis of exclusion.[40A]

SYSTEMIC ASSOCIATIONS

An association between multifocal choroiditis and Epstein–Barr virus systemic infection has been suggested.[41] Immunoglobulin M antibodies directed against the viral capsid antigen or the Epstein–Barr early antigen were present in ten patients in one series—similar antibodies were not present in controls. A second investigation could not confirm this.[42] It has been suggested that Epstein–Barr virus triggers an immune response that results in persistent intraocular inflammation. However, the antibodies to viral capsid antigen and Epstein–Barr early antigen may be present in normal individuals who do not have multifocal choroiditis.[41] Some patients who have multifocal choroiditis also have known sarcoidosis or later are diagnosed with sarcoidosis. These cases may be indistinguishable from the group with idiopathic etiology.

TREATMENT

Treatment of multifocal choroiditis with panuveitis is with topical, periocular, or systemic glucocorticoids, which may be used to reduce anterior segment and vitreous inflammatory activity, macular detachment, or edema. Choroidal neovascularization may be treated with laser photocoagulation, photodynamic therapy, or glucocorticoid therapy (which appears to be of some value), although spontaneous involution of choroidal neovascularization is not uncommon. Laser photocoagulation may be associated with an increase in inflammatory response, which in itself may be the underlying initiator of choroidal neovascularization.[38] [39] Subfoveal choroidal neovascular membranes may be removed surgically. The value of this intervention for ocular histoplasmosis and idiopathic choroidal neovascularization is being investigated in a randomized trial.

COURSE AND OUTCOMES

Multifocal choroiditis and panuveitis waxes and wanes, but progressive loss of vision may take place. Glucocorticoids alone may become insufficient to control intraocular inflammation. Macular disciform scarring may occur. Severe cases of subretinal fibrosis may develop and resemble subretinal fibrosis uveitis syndrome.[38] [39] Thus it is felt by some investigators that multifocal choroiditis with panuveitis and subretinal fibrosis with uveitis represent the same disease but a different intensity of subretinal fibrotic reaction.[38] [39]

Usually, little anterior segment or vitreous inflammation occurs. On ophthalmoscopic examination, small, yellow-white lesions at the level of the choroid or pigment epithelium are present in the posterior pole. Often a serous detachment of the retina overlies active lesions ( Fig. 182-9 ). The lesions “heal” to form atrophic scars of variable pigmentation. Choroidal neovascular membranes may develop from these healed, atrophic, or pigmented scars. If choroidal neovascularization occurs in the macula or near the fovea, serious vision loss may result.[43] Vision also may be affected if the acute phase lesions develop underneath the fovea. [43]

DIAGNOSIS

Diagnosis is based on typical ocular findings; laboratory evaluation is not helpful. Fluorescein angiography of acute lesions reveals early hyperfluorescence and staining, and leakage into the subretinal space if an overlying serous detachment is present. Choroidal neovascularization also shows late leakage.[43]

DIFFERENTIAL DIAGNOSIS

The differential diagnosis is the same as that for multifocal choroiditis and panuveitis (see Box 182-6 ). The lesions also may resemble myopic macular changes and myopic choroidal neovascularization. Many people believe choroiditis and panuveitis and punctate inner choroidopathy represent the same entity.

TREATMENT

When vision is decreased because of serous retinal detachment, systemic or periocular glucocorticoids may be given. Usually, however, the acute phase of the disease is self-limited and treatment is unnecessary. Treatment of extrafoveal macular choroidal neovascularization using focal laser photocoagulation is often warranted to prevent visual loss.[43] Surgical removal of subfoveal membranes may be helpful in selected cases. Photodynamic therapy may be helpful.

COURSE AND OUTCOMES

The visual prognosis of patients who have punctate inner choroidopathy is guarded. If subfoveal lesions and choroidal neovascularization do not occur, visual acuity is usually better than 20/40 (6/12). Recurrences are common. Because there are similarities between punctate inner choroidopathy, multifocal choroiditis and panuveitis, and subretinal fibrosis and uveitis, all three are believed by some investigators to be part of a spectrum of one or more related diseases.[43]

ACUTE RETINAL PIGMENT EPITHELIITIS

EPIDEMIOLOGY AND PATHOGENESIS

Acute retinal pigment epitheliitis is a rare condition that affects young adults in the second to fourth decades of life.[44] Patients usually report minimal to severe visual loss in one eye. Bilateral involvement can occur.

Figure 182-9 Punctate inner choroidopathy. White, punctate chorioretinal lesions in the macula with overlying serous retinal detachment of the fovea in the right eye of a 20-year-old myopic woman. (Courtesy of Richard R. Ober.)

Figure 182-10 Retinal pigment epitheliitis. A discrete cluster of gray-to-yellow, outer retinal lesions in the central macula of the right eye of a 27-year-old woman.

OCULAR MANIFESTATIONS

Anterior segment examination is normal; no vitreous cells are seen. Ophthalmoscopy reveals discrete clusters of small, brown or gray spots in the involved macula ( Fig. 182-10 ). Usually, from two to four spots occur; occasionally, a yellow or white halo may surround some of the spots. Resolution is gradual but usually complete within 6–12 weeks, and visual acuity often returns to normal levels. The acute lesions become blacker. However, some pigmented spots may actually appear faint and be more difficult to see as they resolve.

DIAGNOSIS

A ring of hyperfluorescence is seen on fluorescein angiography to surround the hypofluorescent acute lesions. With resolution, the hyperfluorescence persists and represents window defects from retinal pigment epithelial derangement. Electrophysiological testing results are normal.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of acute retinal pigment epitheliitis is given in Box 182-7 .

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Differential Diagnosis of Acute Retinal Pigment Epithelitis

Rubella retinitis

Acute macular neuroretinopathy

Punctate inner choroidopathy

Central serous retinochoroidopathy

COURSE AND OUTCOMES

Because the disease process is self-limited over a period of 6–12 weeks, no treatment is necessary. The visual prognosis for most patients with acute retinal pigment epitheliitis is good—most patients recover to a visual acuity of 20/20 (6/6).

ACUTE MACULAR NEURORETINOPATHY

EPIDEMIOLOGY AND PATHOGENESIS

Acute macular neuroretinopathy occurs mainly in young, healthy women in the second to fourth decades of life.[45] The disease process may be unilateral or bilateral. Rarely it may have recurrences in one or both eyes. A viral prodrome occurs in some patients. Patients complain of decreased vision or paracentral scotomas or both. The exact cause of acute macular neuroretinopathy is unknown. It may represent inner retinal infarction in the central macula. However, no associated cotton-wool spots or similar changes are seen in the acute phases of the disease. Two patients with acute macular neuroretinopathy were noted to have MEWDS at another stage of their lives. A possible association of these two entities remains unproved.

DIAGNOSIS

Ophthalmoscopy reveals one to several small, circular, oval, or petaloid lesions that surround the fovea. These may appear darker red or brown than the surrounding normal macula. Diagnosis usually is made on the basis of the clinical course and appearance of the lesion. Fluorescein angiography is normal. Visual field testing often reveals paracentral scotomas that correspond very accurately to the shape and location of the macular lesions. Electrophysiological testing is normal.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of acute macular neuroretinopathy is given in Box 182-8 .

COURSE AND OUTCOMES

No treatment is effective, but the disease is usually self-limited. Visual acuity improves and the paracentral scotomas decrease in size, however resolution of symptoms may take months. The acute retinal lesions fade but do not resolve completely. The authors have seen one patient who had multiple recurrences in both eyes.

UNILATERAL ACUTE IDIOPATHIC MACULOPATHY

EPIDEMIOLOGY AND PATHOGENESIS

Unilateral acute idiopathic maculopathy is a rare disorder that usually appears in the second to fourth decades of life and affects men and women equally.[46] Most patients have a history of a flu-like prodrome that precedes the onset of visual symptoms.

Differential Diagnosis of Acute Macular Neuroretinopathy

Acute retinal pigment epitheliitis

Multiple, evanescent, white dot syndrome

Acute posterior multifocal placoid pigment epitheliopathy

Central serous chorioretinopathy

Optic neuritis

Old, inner retinal infarcts

Patients often complain of sudden, severe, unilateral central visual loss. A central scotoma is often present on visual field testing. Bilateral cases and eccentric (nonfoveal) cases have been described recently. There may be an association of the disease with hand, foot, and mouth disease and coxsackievirus infection (Jampol, work in progress).

DIAGNOSIS

Ophthalmoscopic examination discloses an exudative detachment of the macula with irregular borders. There is typically a wedge configuration to the serous retinal elevation. In addition, white, gray, or yellow subretinal thickening at the level of the pigment epithelium, beneath the neurosensory retinal detachment, is often present. Careful evaluation of the posterior vitreous may detect cells that overlie the serous retinal detachment.

Fluorescein angiography shows alternating areas of hyperfluorescence and hypofluorescence beneath the neurosensory retinal detachment. In the late phases of the angiogram, hyperfluorescence occurs from both staining at the level of the RPE and pooling of fluorescein in the subretinal space.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of unilateral acute idiopathic maculopathy is given in Box 182-9 .

TREATMENT

Treatment of this condition is not necessary. The natural course is a rapid and spontaneous improvement in vision with resolution of the neural retinal detachment. However, retinal pigment epithelial atrophy and hypopigmentation do develop in the area of the neurosensory retinal detachment. Visual acuity usually improves to 20/25 (6/7.5) or better in the affected eye. As a result of the surrounding areas of hypopigmentation, the macula takes on a bull’s eye appearance after resolution of the disease.

ACUTE ZONAL OCCULT OUTER RETINOPATHY

EPIDEMIOLOGY

AZOOR is a disorder that predominantly affects young women in the second to fourth decades of life.[47] [48] It is characterized by acute loss of zones of outer retinal function. Photopsias are usually present, and the condition may be unilateral or bilateral. Autoimmune disorders such as Hashimoto’s thyroiditis are not uncommon among women with AZOOR.[48]

OCULAR MANIFESTATIONS AND DIAGNOSIS

On initial examination minimal to no fundal changes are seen. Narrow retinal vessels and depigmentation of the RPE are found within months of onset of symptoms, in zones that correspond to the visual field loss. Varying vitreitis also has been described in patients with AZOOR.

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Differential Diagnosis of Unilateral Acute Idiopathic Maculopathy

Idiopathic choroidal neovascularization

Central serous chorioretinopathy

Vogt–Koyanagi–Harada syndrome

Serpiginous choroidopathy

Posterior scleritis

Acute posterior multifocal placoid pigment epitheliopathy

Placoid syphilitic retinitis

Retinal pigment epithelial detachment

Differential Diagnosis of Acute Zonal Occult Outer Retinopathy

Cancer-associated retinopathy

Retinal vasculitis

Syphilitic chorioretinitis

Diffuse unilateral subacute neuroretinitis

Retinitis pigmentosa

Visual field testing shows large, superior, temporal and, occasionally, central zones of visual field loss. The scotomas often increase in size within a few days to weeks and then stabilize. Visual field loss often occurs in both eyes, but can be very asymmetrical. Some improvement may occur.

Fluorescein angiographic findings typically are normal during the early phases of the disorder. Once the retinal pigment epithelial changes occur, pigment mottling and window defects develop in the periphery. The outer retinal dysfunction can be documented by visual field testing and electroretinography, which reveals moderate to severe reduction in a-wave amplitude. Laboratory evaluation is noncontributory.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of AZOOR is given in Box 182-10 .

COURSE AND OUTCOME

No specific treatment exists for AZOOR. Glucocorticoids and antiviral agents have been tried but have not reduced the amount of visual field loss.

Although most patients retain visual acuity of better than 20/40 (6/12), permanent and occasionally severe visual field loss can occur.

RELENTLESS PLACOID CHORIORETINITIS

EPIDEMIOLOGY

RPC is a rare, often bilateral ocular inflammatory disease of unknown etiology affecting patients between the second and sixth decades of life. [49] Men and women are equally affected. When seeking treatment, patients complain of decreased vision, pericentral scotomas, photopsias, floaters and, rarely, pain.

OCULAR MANIFESTATIONS

Varying degrees of anterior chamber and vitreous cells may be seen. Active retinal lesions appear placoid, white to yellow, and similar in appearance to those of APMPPE or serpiginous choroiditis. These lesions tend to occur characteristically in multiples,

Differential Diagnosis of Relentless Placoid Chorioretinitis

Acute posterior multifocal placoid pigment epitheliopathy

Serpiginous choroiditis

Multifocal choroiditis

Birdshot retinochoroidopathy

Vogt–Koyanagi–Harada syndrome

Neoplastic infiltration of the choroids

Syphilitic chorioretinitis

Sarcoid panuveitis

Tuberculous choroiditis

are one disc diameter or less in size, and may affect the mid- and far periphery prior to involvement of the posterior pole, unlike APMPPE or serpiginous choroiditis. [49] Many of these lesions heal over weeks, resulting in superficial chorioretinal atrophy. However, progressive increase in size of subacute lesions and development of new lesions occurs in all patients. Fifty or more lesions can occur throughout the fundus. These lesions eventually can involve the macular region and acutely result in visual loss, metamorphopsia, or scotoma. Subretinal fluid may be seen in association with the acute lesions. When these lesions heal, visual acuity is often preserved even with macular involvement.[49]

Fluorescein angiography shows early hypofluorescence and late hyperfluorescence of acute lesions.

DIAGNOSIS

Diagnosis is based on clinical appearance of retinal lesions and prolonged clinical course. Laboratory evaluation is not helpful. No consistent systemic association has been found.

DIFFERENTIAL DIAGNOSIS

See Box 182-11 .

TREATMENT

In the original report on RPC, glucocorticoids, antiviral agents, and cyclosporine all were used to treat patients. Immune suppression did appear to halt disease activity.[49] With glucocorticoid treatment, healing and improvement in visual acuity are observed, however the disease can recur despite use of glucocorticoids. The best treatment for this condition is unknown.

COURSE AND PROGNOSIS

Growth of subacute lesions and appearance of new lesions occurs from 5 to 24 months after initial diagnosis. Relapses are common. Eventually, most patients develop 50 or more (sometimes hundreds) healed lesions in the periphery and posterior pole. The long-term visual prognosis appears good.[49] Central vision is preserved as a rule.

UNIFOCAL HELIOID CHOROIDITIS

EPIDEMIOLOGY AND PATHOGENESIS

UHC (also called solitary idiopathic choroiditis) is an inflammatory disorder affecting young, healthy, white patients in the first to third decades of life.[50] [51] Males and females are affected equally. The disease appears to be common in the midwestern United States where histoplasmosis is endemic. There has been no clear-cut relationship between this disease and systemic histoplasmosis. It is not clear whether these lesions represent a microbial infection or immunological reaction of the choroid.

1228

Differential Diagnosis of Unifocal Helioid Choroiditis

Histoplasmin choroiditis

Toxoplasma retinochoroiditis

Sarcoid choroiditis

Other less common fungal choroiditis such as from Coccidioides, Cryptococcus, Pneumocystis

OCULAR MANIFESTATIONS

All patients acutely developed a one–disc diameter, yellow-white choroidal lesion with overlying subretinal fluid and occasional subretinal hemorrhages. Patients may have decreased vision or metamorphopsia or both, depending upon the location of the lesion and the presence of subretinal fluid. Anterior chamber and vitreous inflammation is usually absent but occasionally can be marked. The acute choroidal lesion may be 1–2?mm thick. The lesion may grow slightly in size. The lesions thin slightly and become pigmented as they heal. Overlying subretinal fluid resolves. During the chronic phase the lesions become whiter due to subretinal fibrosis. Fluorescein angiography demonstrated leakage and late staining of the acute inflammatory lesions.[50] Choroidal neovascularization may develop.

DIAGNOSIS

Diagnosis is based on age of the patient, symptoms, and clinical appearance. A uveitis work-up is warranted but may not be helpful.

DIFFERENTIAL DIAGNOSIS

See Box 182-12 .

TREATMENT

No treatment for UHC has been proven to be of value.

COURSE AND OUTCOME

Relapses in the disease marked by slight increase in the size of the lesion or increase in subretinal fluid are common and may last from 1 to 18 months. Choroidal neovascularization occasionally may develop. The visual prognosis is variable and guarded, based on the location of the lesion with regard to the macula. [49] Permanent visual loss may occur.

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